The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma.
Clin Cancer Res
; 25(21): 6382-6391, 2019 11 01.
Article
de En
| MEDLINE
| ID: mdl-31182434
ABSTRACT
PURPOSE:
EGFR exon 19 deletion (Ex19Del) mutations account for approximately 60% of lung cancer-associated EGFR mutations and include a heterogeneous group of mutations. Although they are associated with benefit from tyrosine kinase inhibitors (TKI), the relative inhibitor sensitivity of individual Ex19Del mutations is unknown.ExperimentalDesign:
We studied the TKI sensitivity and structural features of common Ex19Del mutations and the consequences for patient outcomes on TKI treatment.RESULTS:
We found that the L747-A750>P mutation, which represents about 4% of all Ex19Del mutations, displays unique inhibitor selectivity. L747-A750>P differs from other Ex19Del mutations in not being suppressed completely by erlotinib or osimertinib, yet is completely inhibited by low doses of afatinib. The HCC4006 cell line (with the L747-A750>P mutation) exhibited increased sensitivity to afatinib over erlotinib and osimertinib, and computational modeling suggests explanations for this sensitivity pattern. Clinically, patients with EGFR L747-A750>P mutant tumors showed inferior outcomes when treated with erlotinib than patients with E746-A750 mutant tumors.CONCLUSIONS:
These results highlight important differences between specific Ex19Del mutations that may be relevant for optimizing TKI choice for patients.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Inhibiteurs de protéines kinases
/
Adénocarcinome pulmonaire
Type d'étude:
Diagnostic_studies
/
Prognostic_studies
Limites:
Animals
/
Humans
Langue:
En
Journal:
Clin Cancer Res
Sujet du journal:
NEOPLASIAS
Année:
2019
Type de document:
Article